Case Study

Reclassifying a case of myelodysplastic syndrome with excess blasts and erythroid dominance with complex karyotype

Ethan J. Gantana, Zivanai C. Chapanduka, Ernest M. Musekwa

Received: 08 Oct. 2024; Accepted: 29 Jan. 2025; Published: 14 May 2025

Copyright: © 2025. The Author(s). Licensee: AOSIS.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

This article reports an interesting case of myelodysplastic syndrome with excess blasts (MDS-EB). The article provides a detailed description of the patient’s clinical and laboratory findings and illustrates the characteristic morphology of myelodysplasia. The case reported here is significant as it highlights that an increased erythroid lineage is no longer a diagnostic criterion in the newer MDS classifications, despite the possibility of its association with a poor prognosis and that it may be part of a biologic continuity with acute erythroid leukaemia. The report also highlights other important differences in the classification of myeloid neoplasms between the different classifications of haematolymphoid tumours.

Contribution: The proposed change in nomenclature from MDS-EB to MDS with increased blasts (MDS-IB) and the replacement of the term ‘myelodysplastic syndrome’ with ‘myelodysplastic neoplasm’ in the new WHO classification (WHO-HAEM5) could justify inclusion in the South African National Cancer Registry and illustrate why these cases can be better classified using the latest classifications.

Keywords: myelodysplastic syndrome; myelodysplasia; myeloid neoplasms; complex karyotype; cytomorphology; ring sideroblasts; erythroid dominance.

Introduction

Myelodysplastic syndromes (MDS) are clonal disorders characterised by cytopenia, ineffective haematopoiesis, lineage dysplasia, recurrent genetic abnormalities in the bone marrow and a high risk of developing acute leukaemia.¹ According to the latest data from the Surveillance, Epidemiology, and End Results Programme (SEER) registry, the annual incidence of MDS is 4.9 per 100 000 people.² In patients aged 65–69 years, it is 13.9 per 100 000 people, with at least 20 cases per 100 000 people aged > 70 years, while in people over 85 years it is 64 per 100 000 people.²Myelodysplastic syndromes with excess blasts account for about 40% of all MDS cases.

Myelodysplastic syndromes entities, as described in the World Health Organization’s Classification (WHO) of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th Edition (WHO-HAEM4R), include specific subtypes based on blast percentage, ring sideroblasts and number of dysplastic lineages.¹ There are significant differences between the 2008 (WHO-HAEM4) and WHO-HAEM4R classifications in the diagnostic approach to myeloid neoplasms with erythroid dominance.

The two new classifications of haematolymphoid tumours, 5th edition of the WHO (WHO-HAEM5) and the International Consensus Classification (ICC) have nomenclature changes and reorganised the classification and defining features of MDS.^3,4

We present a case of myelodysplastic syndrome with excess blasts (MDS-EB) diagnosed according to the WHO-HAEM4R classification. This case underlines the characteristic morphological features, the essential diagnostic investigations and the crucial role of comprehensive risk stratification. Notably, the patient had a complex karyotype with five chromosomal abnormalities, which emphasises the poor prognosis typically associated with this disease.¹

Myelodysplastic syndrome with excess blasts (WHO-HAEM4R) has a poor prognosis with a median survival of 16 months for MDS-EB1 and 9 months for MDS-EB2. About one third of these cases progress to acute myeloid leukaemia (AML), while the remainder die as a result of bone marrow failure.¹

The blast excess and erythroid precursor dominance in this case highlight the important differences in the classification of myeloid neoplasms between the WHO-HAEM4R, the older edition (WHO-HAEM4) and the newer classifications, WHO-HAEM5 and ICC, which are shown in Table 1.

Case

A 63-year-old woman with no significant past medical history presented with general weakness, fatigue, dyspnoea and headache. Complete blood count revealed severe pancytopenia (haemoglobin level of 2.9 g/dL, absolute neutrophil count of 0.26 × 10⁹/L, platelet count of 141 × 10⁹/L), with 4% blasts in the peripheral blood. The peripheral blood smear (Figure 1) showed scanty teardrop red cells and neutrophils with nuclear atypia and hypogranularity.

FIGURE 1: (a–b) Peripheral blood smear (May-Grünwald Giemsa stain at 100× objective magnification). Scanty teardrop cells (a) and neutrophils with nuclear atypia and hypogranularity (b).

Renal function, folate and vitamin B12 levels were normal with a slightly elevated lactate dehydrogenase (LDH) of 430 U/L.

Bone marrow aspirate showed significant dysplasia in all three lineages (Figure 2) with 3% blasts, 65% erythroid precursors, 16% granulocytes, 4% monocytes and 12% non-myeloid cells in the myelogram with an M:E ratio of 1:4. The number of megakaryocytes was increased, with nuclear hypolobation and multinucleation.

FIGURE 2: Bone marrow aspirate smear (May-Grünwald Giemsa [MGG] stain at 100× objective magnification) shows dysmegakaryopoiesis; multinucleation (a) and nuclear hypolobation (b). Dyserythropoiesis, megaloblastoid changes, multinuclearity, nuclear budding, karyorrhexis or nuclear fragments and internuclear bridging (c–g). Dysgranulopoiesis, decreased granules or agranularity, nuclear hypersegmentation, unusually large sizes and vacuolation (g–i). Images have been taken with an Olympus BX53 Microscope, an Olympus DP22 camera and the DP2-SAL standalone camera controller for image processing (Olympus).

Erythropoiesis was markedly increased with significant dyserythropoiesis (megaloblastoid changes, multinucleated forms, nuclear budding, karyorrhexis and internuclear bridging).

Granulopoiesis was reduced with significant dysgranulopoiesis (hypogranularity, nuclear hyposegmentation and hypersegmentation). Perl’s staining showed 52% ring sideroblasts (Figure 3).

FIGURE 3: Iron stain (Perl’s Prussian Blue stain at 100× objective magnification): ring sideroblasts (a, b).

Bone marrow trephine cellularity was estimated at 45%. The blasts in the bone marrow trephine were determined by CD34 immunohistochemistry and totalled 5% of all nucleated cells in the bone marrow.

Because of pancytopenia with bone marrow hypercellularity, trilineage dysplasia, 4% blasts in peripheral blood, 3% blasts in bone marrow aspirate, 5% blasts in trephine biopsy and > 15% ring sideroblasts, MDS with excess blasts-1 (MDS-EB1) was the most appropriate diagnosis according to the WHO-HAEM4R classification.

FISH on the bone marrow aspirate was 94% positive for deletion 5q31, 95% positive for deletion 7q31, 98% positive for deletion 20q12 and negative for trisomy 8.

Karyotyping revealed a hypodiploid complex karyotype with five chromosomal abnormalities in 8 of 10 metaphases analysed: 42, XX, del(5)(q22q35),der(7;17)(p10;q10),-12,-16,-20 [8] / 46, XX [2].

We found an interstitial deletion of the long arm of chromosome 5 between bands 5q22 and 5q35 (red arrow on Figure 4). There was also an unbalanced whole-arm translocation resulting in a derivative chromosome consisting of the short arm of chromosome 7 and the long arm of chromosome 17. The result was a 7(q) and 17(p) monosomy (blue arrows in Figure 4). In addition, monosomy of chromosomes 12, 16 and 20 (green arrows in Figure 4) was detected.

FIGURE 4: Complex karyotype of the patient with a deletion of the long arm of chromosome 5 (red arrow), an unbalanced whole-arm translocation leading to a derivative chromosome consisting of 7p and 17q, as well as a monosomy of 7q and 17p (blue arrows), and monosomies of chromosomes 12, 16 and 20 (green arrows).

Based on the all available data, the final diagnosis of MDS-EB1 was concluded.

Using the revised International Prognostic Scoring System for MDS (IPSS-R) by Greenberg et al., this patient falls into the very high-risk group with a total score of more than six (7.0), which is associated with a median survival of 0.8 years (0.7% – 0.8, 95% confidence interval [CI]; p < 0.001) [hazard ratio of 8.0].⁵ This score is based on the patient’s very poor karyotype (score value of 4), bone marrow blast percentage > 2% to < 5% (1), haemoglobin concentration < 8 g/dL (1.5), platelets >100 × 10⁹/L (0) and absolute neutrophil count < 0.8 × 10⁹/L (0.5). The complex karyotype is associated with a very poor prognosis in MDS according to the Comprehensive Cytogenetic Scoring System (CCSS), which has a median survival of 0.7 years.⁶

The patient was treated conservatively for 3 weeks in a general ward and unfortunately the patient demised within few days after the diagnosis of MDS.

Discussion

Given the markedly increased immature erythroid precursors in this case, the diagnosis of erythroid leukaemia was initially considered, but the WHO-HAEM4R criteria for AML, NOS; acute erythroid leukaemia (erythroid/myeloid subtype) were not fulfilled.¹ In WHO-HAEM4, the diagnosis of AML NOS; acute erythroid leukaemia could be made if ≥ 50% and < 20% of all nucleated bone marrow cells are erythroid precursors and myeloblasts, respectively, and myeloblasts account for ≥ 20% of non-erythroid cells.⁷ In WHO-HAEM4R, these cases are classified as either MDS-EB (if < 20% blasts) or AML (if ≥ 20% blasts), regardless of the number of erythroid precursor cell count (Table 1). The myeloblast percentage is also calculated in relation to all nucleated bone marrow cells or peripheral blood leucocytes and not excluding erythroid cells. AML, NOS; pure erythroid leukaemia is a single category in WHO-HAEM4R and is defined as a neoplastic proliferation of immature cells belonging exclusively to the erythroid lineage. More than 80% of the nucleated bone marrow cells must be erythroid, > 30% are proerythroblasts. In our case, the patient had 65% (> 50% but < 80%) erythroid cells with < 5% blasts in bone marrow but 2–4% blasts in peripheral blood. The diagnosis of MDS-EB1 was made at the time on the basis of the WHO-HAEM4R classification.

Pure or acute erythroid leukaemias share clinicopathological features with MDS subtypes where erythroid precursors exceed 50%, suggesting a biological link and poor prognosis.^8,9 However, it has been shown that MDS with erythroid predominance is not a uniformly aggressive entity.¹⁰ For this reason and because of minor variations unrelated to the disease process (chemotherapy, nutritional deficiencies, EPO administration, subjective counts) that may change the diagnosis between MDS and AML, an erythroid predominance of ≥ 50% and the counting of blasts using only non-erythroid cells have been removed from the newer classifications.¹¹

The boundary between MDS with excess or increased blasts and AML has been redefined in recent editions of the haematolymphoid tumour classifications. WHO-HAEM5 retains the 20% blast cutoff to define AML, with multidisciplinary experts agreeing that adopting a lower cutoff (e.g. 10%) risks overtreatment, while agreeing that MDS-IB2 (peripheral blood blasts 5% – 19% and bone marrow blasts 10% – 19%) can be considered as the AML-equivalent for therapeutic considerations and clinical trials.³ The ICC has introduced a separate category, MDS/AML, which groups MDS-EB2 with AML and assumes a cutoff of 10% blasts in peripheral blood or bone marrow.⁴ This latter category was considered by WHO-HAEM5 although it was not included because of subjectivity and the lack of a gold standard for blast counting and the use of another arbitrary cutoff to define categories. However, a category such as MDS/AML recognises the biological and diagnostic continuity between MDS and AML and means that these patients are eligible for both clinical trials and treatment for MDS and AML. Based on the WHO-HAEM5 classification, this patient would have been diagnosed as MDS with increased blast percentage (MDS-IB)-1 and as MDS-EB based on the ICC, with the available data. As the different classifications are merely a change in nomenclature, this would theoretically not change the treatment of this patient. This also shows that the two classifications are largely in agreement when it comes to grouping for low blast percentages in MDS.

In addition, the ICC and WHO-HAEM5 largely agree in grouping patients based on genetic risk stratification, which both classifications consider superior to morphological assessment of MDS. An important consideration would be if an AML-defining genetic abnormality were detected with a myeloid panel Next Generation Sequencing (NGS), because then the entity would be classified as AML regardless of whether the blasts are < 20% in WHO-HAEM5, which would theoretically require induction chemotherapy. For this reason, NGS using targeted panels such as a myeloid panel, which are now widely available, should be considered at the initial evaluation of all patients with a myeloid neoplasm. Furthermore, the presence of excess blasts is above all MDS subtypes, with the exception of MDS with mutated TP53, which define distinct entities in the ICC and WHO HAEM5 classification because of their poor prognosis. Cases like the one presented here, with an erythroid predominance are often associated with TP53 mutations, but unfortunately no mutation analysis for TP53 was performed in this patient, which could have provided crucial information.¹¹

With a total score of 7, this patient falls into the very high risk group when using the IPSS-R for risk stratification. The IPSS-R has been the global standard for risk stratification of newly diagnosed MDS patients for many years, but does not take into account genetic variants that have prognostic significance.¹² The IPSS-M was developed to incorporate these genetic variants into a genoclinic model that has been shown to perform better than gene models alone or the IPSS-R in predicting MDS outcomes in certain conditions.^13,14 The use of the IPSS-M is particularly important in lower-risk MDS or patients with a normal karyotype, where the presence of an unfavourable genetic variant may refine prognosis.¹⁴ This would have implications for treatment, as the goal of treatment in low-risk MDS is to improve cytopenias and prolong the quantity of life with quality, whereas in high-risk MDS, disease-modifying treatment such as an allogeneic transplant is required to alter the natural history of the disease.¹⁵

The term ‘myelodysplastic neoplasms’ (still abbreviated as MDS) replaces the term ‘myelodysplastic syndromes’ in WHO-HAEM5 to emphasise the neoplastic nature of MDS and harmonises the terminology with myeloproliferative neoplasm (MPN). This change will allow MDS to be included in the South African National Cancer Registry, as there is currently no public information on the incidence and prognosis of MDS in South Africa.¹⁶ For this reason, the renaming of this case as MDS-IB1 using WHO-HAEM5 may be more appropriate.

Conclusion

This is an interesting case of MDS-EB1 or MDS-IB1 with exemplary morphology, showing most of the WHO-defined dysplastic changes in all three lineages and the poor outcome associated with this entity. The case highlights the important classification changes to consider in the diagnosis of myeloid neoplasms in which blasts are increased in the peripheral blood or bone marrow and erythroid precursors account for > 50% of nucleated bone marrow cells. It is significant to emphasise that increased erythroblastic lineage is not a diagnostic criterion in the current MDS classification, despite the possibility that such MDS is associated with a poor prognosis and may be part of a biologic continuity with acute erythroid leukaemia.The nomenclature change proposed by WHO-HAEM5 to highlight the neoplastic nature of MDS may warrant inclusion in the National Cancer Registry to provide information on trends, incidence and prognosis of this disease in South Africa.

Acknowledgements

The authors would like to acknowledge Daphne Taylor (Human Genetics, National Health Laboratory Service (NHLS), Groote Schuur Hospital, Cape Town) for the karyotype images of this case.

The authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article.

E.J.G. wrote the original draft and was responsible for the visualisation and project administration. E.J.G., Z.C.C. and E.M.M. contributed equally to the discussion, review and editing of subsequent drafts.

Ethical clearance to conduct this study was obtained from the Stellenbosch University, Health Research Ethics Committee (No. C22/10/032). Informed consent was waived as the report does not contain any identifying information that could be linked to the patient.

This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

Data sharing is not applicable to this article as no new data were created or analysed in this study.

The views and opinions expressed in this article are those of the authors and are the product of professional research. The article does not necessarily reflect the official policy or position of any affiliated institution, funder, agency or that of the publisher. The authors are responsible for this article’s results, findings and content.

References